10
Bioorganic Chemistry
2.2.3
Hydrophobic Effect
The hydrophobic effect refers to the ten-
dency of nonpolar species to associate
in water and thereby limit the extent of
their water contact. Macroscopically, this
is manifested in the separation of oil from
water. Microscopically, this is manifested
by the tendency for side chains of nonpo-
lar amino acids to cluster in the interior of
proteins, away from water contact. In a va-
riety of studies, it has been demonstrated
that there is a linear dependence on the
amount of nonpolar surface a molecule
has and its tendency to prefer nonpolar
environments. Although this is a com-
plex and by no means a fully understood
phenomenon, it appears to be entropically
driven. A nonpolar surface cannot hydro-
gen bond effectively with water molecules.
Theresu
l
tistha
tthereisanorder
ingo
f
water molecules around nonpolar species,
with each water orienting so as to max-
imize the number of hydrogen bonds.
Th
er
e
su
l
ti
sth
a
tth
e
s
ew
a
t
e
r
sa
r
el
im
-
ited in their range of motion, resulting
in a decrease in entropy and therefore an
(free) energetically unfavorable situation.
The more nonpolar molecules cluster, the
less (non–hydrogen bonding) surface they
expose to water and the less of this water
ordering takes place.
2.2.4
van der Waals’ Interactions
In addition to the strong interactions of
charges found in salt bridges and hydrogen
bonds, there are weaker forces that allow
principally uncharged species to also have
attractive (and repulsive) interactions with
other species. This is so because although
these nonpolar species have no formal
charge or dipole, they can transiently form
a dipole due to random fluctuations of elec-
trons within them. These transient dipoles
can interact with other transient (and non-
transient) species. In general, because of
the random generation of these dipoles,
van der Waals’ forces are rather weak
forces, acting over short distances. A clas-
sical example of van der Waals’ attraction
is between the stacked bases of DNA.
2.2.5
Conformational/ConFgurational
Aspects
In addition to all of the speciFc attractive
and repulsive forces described above, there
are several other important factors that in-
fluence molecular associations. ±irst of all,
there is conformational free energy. If a
molecule has to adopt a highly strained
conformation in order to bind productively
to its host, its afFnity for the host will be de-
creased relative to a similar molecule that
can make the same interactions without
adopting the strained conformation. ±ur-
thermore, if a molecule can adopt many
conformations (i.e. a so-called conforma-
tionally flexible molecule) and only a few of
these can productively bind, then its afFn-
ity too will be decreased relative to a rigid,
conformationally restricted molecule that
can make similar interactions.
±inally, there is the rotational/translat-
ional entropy loss that accompanies bind-
ing. This is the free-energetic cost of
preventing a molecule from moving freely
in solution. This is a Fxed cost in the
sense
that
it
will
always
have
to
be
paid when two molecules associate. Be-
fore two molecules associate, they each
have three rotational and three transla-
tional (movement through space) degrees
of freedom, for a total of 12. These
degrees of freedom are related to the
system’s entropy, the greater the num-
ber of degrees of freedom, the greater the
randomness (and entropy). After the com-
plex forms, there is essentially a single
species having three degrees of rotational
and three degrees of translational free-
dom. The overall entropy is decreased,
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